and heat hyperalgesia after incision in mice.

67 Further confirmation for an unique peripheral

sensitization process after incision came from a study investigating 84 mRNAs from the neurotrophins and
inflammatory cytokines families in skin, muscle, and DRG after plantar incision. As demonstrated, most
alterations in the mRNA expression are present in incised skin and muscle, less in the DRG. They occur
within the first 48 hours after incision when the mechanical and heat hyperalgesia, as well as guarding
pain, is most obvious. In particular, genes for wound healing, reinnervation, and the immune response
are differently expressed in comparison to other pain models.164 More examples supporting this are
shown in Table 1. Only recently peripheral inflammatory cell responses were investigated after incision
injury in animals. For instance, migration of neutrophilic granulocytes (NGs) into tissue traumatized by
incision occurs shortly after surgery, reaching a maximum at 24 hours and declining rapidly to baseline
within 3 days. Neutrophilic granulocytess release many wellknown proinflammatory mediators and
contain endogenous opioid peptides (met-enkephalin and b-endorphin).146 Sahbaie and colleagues
demonstrated that the systemic depletion of NGs (with Gr-1 antibody) reduced the paw edema and the
interleukin1b (IL-1b) concentration, but increased significantly the heat hyperalgesia for 24 hours and did
not alter the mechanical hyperalgesia after plantar incision in mice.153 This suggests a role of endogenous
opioids (released by NGs) for incisional pain similar to that shown in inflammatory pain models.147
However, another study from Carreira et al. used the same method to deplete NGs but showed
attenuation of mechanical hyperalgesia after incision; they suggested the role of CXCL-1-CXCR1/2
recruitment of NGs after incision. Presumably, proinflammatory mediators from NGs (IL-1b and C5a) may
play a role for hyperalgesia after incision. Thus, as the local concentration of C5a after the incision is
increased, this complement factor may provide a novel target for analgesic drug development. However,
the exact role of NGs in postoperative pain is currently unclear because of the contradictory results of
both NGdepletion studies. The prevention of mast cell degranulation (mast cell membrane stabilization
with Cromoglycate) or depletion of mast cell mediators (with Compound 48/80 prior to incision), thus
inhibiting the effect of histamine, 5-HT, and tryptase (a serine protease localized exclusively in mast cells)
reduce the mechanical hyperalgesia and nonevoked pain in mice. Similar effects are observed by
administration of tryptase-binding receptor antagonist (protease-activated receptor 2, PAR2). These
results suggest a role of mast cells contributing to hypersensitization after incision. However, it should be
noted that the mast cell degranulation alone seems insufficient to promote pain (eg, allergies, some drug
administration).

2.2.3. Neuroplastic changes in the brain after incision

Our understanding of the processing of pain in the human brain has improved significantly105;
however, activity and neuroplasticity in the pain matrix after incision contributing to pain-related behavior
remains poorly understood. A recent study in animals indicates directly how the brain reacts to an incision
compared to inflammation by using functional magnetic resonance imaging to assess oxygenation levels
of the blood as an indirect measure of neural activity and functional magnetic resonance spectroscopy.5
Mechanical stimulation of the incised hind paw showed blood oxygen level dependent (BOLD) signals,
which differed significantly in quantity and quality to BOLD signals related to mechanical stimulation of
the hind paw after CFA inflammation. Similarly, BOLD signals after electrical stimulation in both animal
models differed to mechanical stimulation.5 However, GABA levels (measured with functional magnetic
resonance spectroscopy) increased in both pain models within the thalamus, during rest and during
mechanical stimulation.5 Thus, the thalamus might play a central role for hyperalgesia regardless of the
pain entity and GABA neurotransmission might be involved. Further imaging studies investigated central
neuroplastic changes relevant for the development of more chronic pain after incision. Human functional
magnetic resonance imaging studies confirmed the role the thalamus139 and indicated a lack of
descending inhibition in enhanced pain responses of patients with chronic pain after incision. By using the
positron emission tomography-method, Romero et al. demonstrated long-lasting changes in glucose
metabolism in central painrelated areas and opioid-related pathways up to 21 days after incision. The
metabolic changes in the pain matrix were positively correlated with hypersensitivity caused by naloxone
injection in rats which received remifentanil anesthesia earlier. This suggests long-lasting neuroplastic
adaptations in central opioid circuits possibly contributing to chronic pain after incision. Systemic
administration of gabapentin, or inhibition of ERK within the anterior cingulate cortex (ACC) early after
surgery, but not systemic morphine, reduced incision-induced anxiety. Interestingly, ERK-inhibition
reduced anxiety-like behavior and mechanical hyperalgesia early after surgery (1 hour), but (different to
inflammatory and neuropathic pain) in the later phase (6 hour), it exclusively reduced anxiety. A recent
study showed that presurgical or postsurgical exposure to stress factors like immobilization and force
swimming test does not change the basal pain perception to different stimuli, such as mechanical, hot
and cold, but prolongs the duration of incision-induced hyperalgesia after incision. By blocking spinal
glucocorticoid receptors or removing the adrenal glands, stress-induced prolongation of incision-induced
hyperalgesia was abrogated. These results indicate a direct connection between the activation of the
hypothalamic-pituitary-adrenal axis through presurgery and postsurgery stress and duration of incision-
induced hypersensitivities. Maternal adversity in the form of perinatal stress and depression may also
activate the hypothalamic-pituitary-adrenal system and increased incisional pain in adult rats. Thus, acute
stress might be—similar to other psychological factors—relevant for the transformation of acute into
chronic pain after surgery.

2.3. Epigenetic modulation after incision

In recent years, a growing body of publications has examined the potential of the epigenetic
modulation, such as DNA methylation, histone acetylation and noncoding RNA, for chronic pain
conditions. Some epigenetic results are now available for acute postoperative incisional pain in animals.
An incision seems to induce changes in global DNA methylation, which leads to increased incision-induced
hyperalgesia. Peripheral and spinal inhibition of a DNA methyltransferase via 5-Aza-2´- deoxycytidine led
to attenuation of the mechanical and heat hyperalgesia and reduced hind paw swelling.170 Furthermore,
epigenetic modulation of spinal Bdnf2 (brain-derived neurotropic factor) and Pdyn2 (prodynorphin) genes
via acetylated Histone H3K9 in mice under chronic opioid exposure seems to be involved in opioid
tolerance after incision.154 Notably, different histone deacetylase inhibitors, such as suberoylanilide
hydroxamic acid or trichostatin A, attenuated heat hyperalgesia7 or 8 E.M. Pogatzki-Zahn et al.·2 (2017)
e588 PAIN Reports® mechanical hyperalgesia159 in an inflammatory (CFA) and in a neuropathic pain
model, but exacerbated mechanical hyperalgesia after incision in mice.169 Taken together, these first
epigenetic results suggest that peripheral and spinal epigenetic modulation are involved in increased
postoperative nociceptive sensitization (Fig. 2). The additional influence of epigenetic regulation by drugs
(eg, opioids) or environmental input could induce long-lasting changes in the pain system, one possible
cause for a transformation from acute to chronic conditions.

2.4. New drugs in the pipeline In recent years, nonclassical active pharmaceutical ingredients from
venoms of spiders128,163 or from other sources66,82,84,100,106,122,155,180,200,201 have been tested
for their potential to reduce mechanical/heat hyperalgesia and/or nonevoked pain or gait abnormalities
after incision. Some substances act directly at receptors, such as the vitexin, a C-glycosylated flavone
present in several medicinal herbs, which binds to GABAA and opioid receptors.200 Some more recent
studies report that curcumin (diferuloylmethane), a phenolic constituent of turmeric, reduces incisional
inflammation, nociceptive hypersensitivity,201 spontaneous pain, and functional gait abnormalities by
increasing the level of TGF-b in incisional skin.155 Other substances block spinal N-type voltage-sensitive
Ca21 channels and reduce mechanical hyperalgesia after incision without altering the normal nociceptive
sensitivity, eg, venom of the Brazilian armed spider Phoneutria nigriventer. 128 These nonclassical active
pharmaceutical substances have characteristics making them suitable as potential candidates for the
development of new analgesics for postoperative pain.

2.5. Challenges in the translation of animal studies to man

The translation of findings from animals to patients (and back) is one of the greatest challenges
in modern (pain) research. Previous studies have shown that the direct translation of results from rodent
experiments is difficult and should be performed and interpreted with caution.111 One major
disadvantage of many animal pain models is that they are not representing the pain etiology or pain entity
they are translated to.111,112 The development of more sophisticated animal models, mimicking human
pain conditions to improve bench-to-bedside translation, is part of the current discussion.24,34,111 The
same, in fact, relates to human experimental pain models and their translation to patients and needs
attention as well.103 Furthermore, the portfolio of behavioral pain measurements in animals does not
represent well clinically relevant pain aspects in humans. For several years, we and others assess
spontaneous pain behavior in rats after incision representative of pain at rest in patients.19,133,143,144
Hyperalgesia to pinprick stimuli are assessed in rats frequently; interestingly, the same stimuli are used to
assess hyperalgesia around a surgical wound in patients,37,167 the mechanisms behind this might be
relevant for central sensitization and prolongation of pain after surgery and are therefore useful to
study.44,93 More recently, movement-evoked pain and painrelated anxiety and depression are explored
in animals after incision; presumably, these might be other translatable pain-related behaviors and should
be focused on in the future.111,112,176 Together, adequate animal pain models (eg, incisions for surgical
pain,18,19) and relevant pain behavior assessed in these models combined with experimental human
studies139 will pave the way for a refined and more applicable bench-to-bedside translation in
postoperative pain.

3. Evidence for clinical management of postoperative pain

The preceding part of this article has outlined quite clearly that postoperative pain as a
manifestation of acute pain is markedly more complex than originally thought. The complexity of
postoperative pain requires, therefore, considerably more than simply applying opioids as required. It is,
therefore, not surprising that there is now a large scientific evidence basis for the management of
postoperative pain. This has been summarized recently in the fourth edition of the document “Acute Pain
Management: Scientific Evidence”, published by the Australian and New Zealand College of Anaesthetists
and its Faculty of Pain Medicine.157 The sheer size of this document reflects the complexity quite well;
the document has nearly 650 pages, assesses over 8500 references, and condenses the evidencebased
information in 669 key messages. It is obvious that it would be impossible to summarize that entire
document in this article. The article will, therefore, concentrate on overarching key strategies and specific
treatment options as far as they are of more general importance.
 3.1. Multimodal analgesia

The concept of multimodal (“balanced”) analgesia has been introduced into the management of
postoperative pain more than 20 years now.79 The concept suggests that it is superior to combine
analgesics with different modes or sites of action, as such combinations will improve analgesia, reduce
opioid requirements (so-called “opioid-sparing” effect), and thereby reduce the adverse effects of
opioids.194 This concept is in line with the observations in basic science models that combinations of, for
example, peripherally and centrally acting analgesic compounds are of value here. In addition, such
multimodal approaches show further benefits with regard to other postoperative outcomes. Just to
mention a few examples here, after total knee joint replacement, multimodal analgesia increases patient
satisfaction scores and permits earlier achievement of milestones of physical therapy.87 Similarly, after
spinal surgery, use of multimodal analgesia improves postoperative mobilization.108 In view of data
showing that increased opioid use, with resulting opioid adverse effects (in particular nausea, vomiting,
and constipation), delays recovery after surgery and thereby leads to extended hospital stay with
increased costs,124 multimodal analgesia would reduce such complications, speed up recovery, and
possibly even reduce hospital costs. This is nicely reflected in the fact that more or less all approaches
using enhanced recovery after surgery protocols include multimodal analgesia concepts as one
component.78 However, it has to be acknowledged that multimodal analgesia by itself does not result in
early rehabilitation or enhanced recovery after surgery. To achieve these goals, multimodal analgesia
needs to be integrated into a holistic and multidisciplinary approach to the postoperative period.119 In
particular, again the importance seems to be the opioid-sparing effect, as avoidance of oral opioids in the
postoperative period after colorectal surgery reduces the length of stay.2 This is confirmed by other data
that show that opioid-sparing analgesic techniques reduce postoperative ileus.11 In this context, it is
interesting to look in more detail at which compounds are actually useful components of multimodal
analgesia and should thereby be combined with opioids.

3.2. Reduction of peripheral sensitisation due to inflammation

3.2.1. Nonsteroidal anti-inflammatory drugs

As outlined before, peripheral sensitisation of nociceptors leading to primary hyperalgesia is an

important contributor to postoperative pain. It is, therefore, not surprising that in clinical reality drugs
which are reducing peripheral prostaglandin concentration and thereby leading to reduced peripheral
sensitisation are a useful component of multimodal analgesia. In randomized controlled trials52 and their
meta-analyses, these drugs fulfill all 3 requirements on multimodal analgesia, ie, improved analgesia,
reduced opioid requirements, and reduced adverse effects of opioids.109 A reduction of postoperative
nausea and vomiting, one of the most disturbing adverse effects of opioids in the early postoperative
period, is reported. COX-2 selective nonsteroidal anti-inflammatory drugs (NSAIDs) (coxibs) have similar
efficacy to nonselective NSAIDs.113 However, they are superior in the postoperative setting because of
reduced adverse events. With regard to bleeding complications, coxibs lack platelet inhibition116 and
therefore cause less postoperative blood loss than nonselective NSAIDs64 and are comparable to
placebo.101 Furthermore, these compounds show a gastric ulceration rate similar to placebo and
significantly lower than nonselective NSAIDs in high-risk patients, even for short-term use.56 Coxibs do
not cause bronchospasm in patients with NSAID-exacerbated respiratory disease, a complication, which
can occur with nonselective NSAIDs.114 Concerns about cardiovascular complications of coxibs, identified
with rofecoxib and leading to its withdrawal,21 have not eventuated with short-term use of parecoxib158
or even long-term use of celecoxib.123 The effect of NSAIDs may be enhanced by the addition of
paracetamol as the combination of paracetamol and NSAIDs is more effective than either compound
alone.

3.2.2. Corticosteroids

Dexamethasone as an anti-inflammatory corticosteroid is widely used in anesthetic practice to

prevent nausea and vomiting.38 Other effects include an improvement of the quality of recovery and
reduced fatigue.117 In addition, dexamethasone in therapeutic doses reduces postoperative pain scores
and opioid consumption.179 However, these effects are small and only statistically significant and might
not be of clinical relevance. In addition, there is still an ongoing debate about potential risks of
perioperative steroid administration with regard to induction of hyperglycemia, increasing risk of infection
and bleeding and possibly malignancy recurrence.

3.3. Reduction of secondary hyperalgesia due to central sensitization

As outlined in detail in the preceding part of the article, it is obvious that central sensitisation
plays a much more relevant role in the development of postoperative pain than previously thought. 10
E.M. Pogatzki-Zahn et al.·2 (2017) e588 PAIN Reports® Findings in this setting illustrate that contrary to
common beliefs, central sensitisation can occur within a very short time span and can significantly
contribute to the overall picture of a postoperative pain state. It is therefore not surprising that there is
increasing interest in the use of medications, which are attenuating such states of secondary hyperalgesia
due to central sensitisation. A number of these compounds have become components of clinically useful
multimodal analgesia. These include the NMDA receptor ketamine, the alpha-2-delta ligands pregabalin
and gabapentin and the alpha-2-adrenergic agonist’s clonidine and dexmedetomidine.

3.3.1. Ketamine

Ketamine is a noncompetitive antagonist of the NMDA receptor when used in subanaesthetic

doses. Meta-analyses support the use of perioperative IV infusions of low-dose ketamine (in the range of
around 0.1 mg·kg21 ·h21 ) with resulting improved analgesia, an opioid-sparing effect and reduction of
opioid side effects such as postoperative nausea and vomiting.89 The benefits of ketamine are, in
particular, seen in patients after major surgeries that are suffering severe pain (VAS .7/10). This explains
why these benefits have been shown after thoracic and upper abdominal and major orthopedic surgery.
In addition, not only in laboratory settings but also in the clinical settings, NMDA receptor antagonists
such as ketamine are reducing the development of opioid-induced hyperalgesia, for example after
remifentanil use.185 It is, therefore, not surprising that ketamine is also a useful analgesic in the settings
of patients with established opioid tolerance13,175 and preoperative high opioid use.102 Similar findings
with regard to opioidsparing and improvement of analgesia have also been found with a perioperative
infusion of magnesium which has to be regarded as another NMDA-receptor antagonist.118 Last, not
least, there are data supporting the effect of perioperative ketamine in reducing the incidence of chronic
postsurgical pain (see preventive analgesia).

3.3.2. Alpha-2-delta ligands

The alpha-2-delta ligands pregabalin and gabapentin, which were developed for the treatment of
neuropathic pain where they find their most relevant indication, have also been shown to have an effect
on central sensitisation and are, therefore, for example, indicated in the treatment of fibromyalgia with
FDA approval. In this context, it is, therefore, not surprising that for both compounds there is evidence
from meta-analyses supporting their role as a component of multimodal analgesia.110,172 Data show
reduced pain scores as well as reduced opioid consumption and thereby reduced adverse effects of
opioids. This beneficial effect can be achieved with a single preoperative dose. In addition, the anxiolytic
effect of these drugs should be taken into consideration and might be an additional beneficial factor,130
again in analogy to the basic science findings.

3.3.3. Alpha-2-adrenergic agonists

Perioperative systemic use of alpha-2 agonists such as clonidine and dexmedetomidine also fulfills
the criteria for successful multimodal analgesia resulting in reduced pain intensity, opioid consumption,
and nausea.15 However, with their use, potential adverse effects such as hypotension and bradycardia
and possibly dose-dependent sedation need to be considered. In conclusion, the concept of multimodal
analgesia is supported by a large clinical data set, which shows that addressing both peripheral and central
sensitisation after surgical incision leads to improved analgesia with reduced opioid requirements and
thereby opioid side effects. Current data do not permit a decision on which combinations of how many
components may comprise multimodal analgesia after what kind of surgical incision. However, from a
practical point of view it seems to become increasingly routine in the setting of acute pain services to use
an NSAID (best seems to be a COX-2 selective one) routinely, paracetamol and (eg, before major
procedures, in healthy patients) an alpha-2-delta ligand as standard components of multimodal analgesia
with rescue opioid being available on top of this. Other components such as ketamine and alpha-2
agonists are used in specific indications. The role of corticosteroids is not yet fully established in this
setting and requires further investigation.

3.4. Procedure-specific postoperative pain management

The basic science data presented above suggest that depending on the type and location of the
incisional model, different pain states result. Again this is confirmed by clinical data which show that
analgesics may have different efficacies in different surgical settings.57 This is true even for a simple
analgesic like paracetamol, which is significantly less effective after orthopedic surgery (relative risk
reduction 1.87) than after dental extraction (relative risk reduction 3.77). Current large meta-analyses
used to calculate the number needed to treat of analgesic agents might pool data from different
postoperative pain states and thereby ignore the specific effects of a specific analgesic in a specific
postoperative pain state.57 In addition, it has to be acknowledged that different surgical procedures do
not only cause different pain states but also pain states of different severities in different locations. These
observations and the support by basic science have led to the development of the concept of procedure-
specific postoperative pain management. Treatment pathways for the management of postoperative pain
after different surgical procedures can be developed in an evidence-based fashion by analyzing the
literature specific to the respective procedure.72 Guidelines for a number of surgical procedures of
different types have been developed by the PROSPECT initiative with the consideration of primarily
procedure-specific evidence (www. postoppain.org). The guidelines can be found at the website of this
initiative, and most of the guidelines have been accompanied by publications in the peer-reviewed
literature with regard to these specific procedures
 3.5. Acute postoperative neuropathic pain

Neuropathic pain is still widely considered a chronic pain state. However, clinical experience and
clinical data, as well as the animal data provided above, are showing that neuropathic pain can occur
acutely and can be a component of postoperative pain. The literature shows that for example following
sternotomy 50% of patients presented with dysaesthesia in the early postoperative period as a
manifestation of acute neuropathic pain.4 As in other chronic neuropathic pain states, a manifestation of
neuropathic pain is accompanied by increased pain severity. Similarly, after cancer surgery, use of a
screening tool in a prospective setting found acute neuropathic pain in the first week postoperatively in
around 10% of the cases.68 A case series in a general surgical population identified an incidence in the
range of 3% to 4%.151 It is, therefore, relevant for clinicians looking after postoperative 2 (2017) e588
www.painreportsonline.com 11 patients (and even more so after post-traumatic patients) to identify a
neuropathic pain component, which might then require appropriate treatment, for example, with alpha-
2-delta ligands or ketamine on top of commonly used opioids.

3.6. Preventive analgesia

Nerve injury leading to acute neuropathic pain is one of the major risk factors for the progression
of acute to chronic pain.1 Chronic postsurgical pain is much more common than usually thought and the
estimated incidence of chronic severe pain with an intensity of more than 5/10 occurs in 2% to 10% of
patients after surgery.157 Besides nerve injury as a risk factor, other risk factors include preexisting
preoperative pain, preoperative anxiety, catastrophizing as well as genetic predisposition. Postoperative
factors are again severe acute postoperative pain and psychosocial risk factors similar to those in the
preoperative setting. This is in line with some of the observations with regard to behavioral changes
observed in animal studies. In view of nerve injury as a risk factor, it is not surprising that a large
percentage of chronic postsurgical pain has features of neuropathic pain.71 With regard to the prevention
of such pain states, there has been a significant change in concepts away from the previously supported
pre-emptive analgesia approach to a preventive analgesia approach.91 Pre-emptive analgesia is defined
as a preoperative treatment, which is more effective than the identical treatment administered after the
incision. The key difference is the timing of the administration. It has become increasingly obvious that
preventive analgesia, ie, an analgesic effect beyond its expected duration is a more useful approach. For
practical terms, this has been defined as analgesia which persists beyond 5.5 half-lives of a medicine.76
In the context of prevention of chronic surgical pain, it is also important to maximize the benefits of any
analgesic strategy by continuing the treatment into the postoperative period as long as the sensitising
stimulus persists. With regard to the preventive effect on chronic postsurgical pain, best data are available
for the use of regional or neuraxial analgesia. A meta-analysis supports the use of epidural analgesia after
thoracotomy and the use of paravertebral blocks after breast cancer surgery.6 Data at lower levels of
evidence support the use of spinal anesthesia over general anesthesia for Caesarean section121 and
hysterectomy,17 as well as the use of epidural analgesia after major abdominal surgery92 and for
amputations with regard to the reduction of phantom limb pain.54 Interesting specifically for phantom
limb pain is the idea of decreasing the already existing preoperative pain to reduce phantom limb pain
after surgery; here, both epidural analgesia and systemic opioids seem to be effective.75 Other data
support the use of perioperative local anesthetics for wound infiltration.14,16 However, it is important in
this context to realize that intravenous lignocaine also has preventive effects on acute postoperative
pain12 and in one small study reduced chronic postsurgical pain.58 Further evidence supports the use of
ketamine as a preventive treatment for chronic postsurgical pain. A meta-analysis of 14 rather small
randomized controlled trials shows a reduction of chronic postsurgical pain at 3 and 6 months, in
particular if ketamine is administered for more than 24 hours perioperatively.29 With regard to the alpha-
2-delta ligands gabapentin and pregabalin, there may be an effect on preventing chronic postsurgical pain;
however, the data are currently rather contradictory and looking at only a few usually small studies with
a large degree of heterogeneity so that uncertainty continues here.29,33 In conclusion, the current
evidence base for the management of acute postoperative pain is significant. Much of the clinical data,
which support certain approaches are in line with findings in the experimental setting. However, there
are a number of discrepancies here and it will be interesting to see if the development of new compounds
based on basic science studies will further help to improve the management of acute postoperative pain.
It remains important to realize that postoperative pain management is not only a humanitarian task to
reduce patient suffering and improve patient satisfaction but that treatment of acute postoperative pain
has the potential to reduce morbidity possibly even mortality after surgery and in parallel enhance
recovery, improve rehabilitation, reduce hospital stay and thereby overall hospital cost.